Erythropoiesis defect observed in STAT3 GOF patients with severe anemia

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11130%2F20%3A10410767" target="_blank" >RIV/00216208:11130/20:10410767 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00064203:_____/20:10410767

Výsledek na webu

<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=jMfv_tjjk5" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=jMfv_tjjk5</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jaci.2019.11.042" target="_blank" >10.1016/j.jaci.2019.11.042</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Erythropoiesis defect observed in STAT3 GOF patients with severe anemia

Popis výsledku v původním jazyce

In summary, we reveal that STAT3 activity in patients carrying the P715L-STAT3 mutation can be modulated by either IL-6 stimulation or targeted inhibition. Furthermore, based on our findings in cell lines, P715L-STAT3 is not constitutively active in patients carrying the mutation. In these patients, STAT3 interacts with proinflammatory binding partners. Finally, P715L-STAT3 GOF manifests with faster kinetic and prolonged STAT3 phosphorylation, causing deviated STAT5 activity in our in vitro model of hematopoiesis. This imbalance in STATs&apos; activity suppresses erythropoietic capacity as evidenced by low erythropoietic potential of peripheral CD342 precursors. The chronic state of severe anemia seen in P1 was accompanied by oligoclonal lymphoid infiltrates in the BM. This observation, together with successful treatment of pure red cell aplasia using a combination of high-dose methylprednisolone, IL-6R inhibitor, and cyclosporine A after the use of a JAK inhibitor, shows that this chronic state of severe anemia can be reversed. This indicates that erythropoiesis in patients with STAT3 GOF mutations is a system under strain, in which inflammatory triggers may unbalance erythroid differentiation and suppress proliferative capacity of red blood cell precursors, rendering patients less able to respond with stress erythropoiesis.

Název v anglickém jazyce

Erythropoiesis defect observed in STAT3 GOF patients with severe anemia

Popis výsledku anglicky

In summary, we reveal that STAT3 activity in patients carrying the P715L-STAT3 mutation can be modulated by either IL-6 stimulation or targeted inhibition. Furthermore, based on our findings in cell lines, P715L-STAT3 is not constitutively active in patients carrying the mutation. In these patients, STAT3 interacts with proinflammatory binding partners. Finally, P715L-STAT3 GOF manifests with faster kinetic and prolonged STAT3 phosphorylation, causing deviated STAT5 activity in our in vitro model of hematopoiesis. This imbalance in STATs&apos; activity suppresses erythropoietic capacity as evidenced by low erythropoietic potential of peripheral CD342 precursors. The chronic state of severe anemia seen in P1 was accompanied by oligoclonal lymphoid infiltrates in the BM. This observation, together with successful treatment of pure red cell aplasia using a combination of high-dose methylprednisolone, IL-6R inhibitor, and cyclosporine A after the use of a JAK inhibitor, shows that this chronic state of severe anemia can be reversed. This indicates that erythropoiesis in patients with STAT3 GOF mutations is a system under strain, in which inflammatory triggers may unbalance erythroid differentiation and suppress proliferative capacity of red blood cell precursors, rendering patients less able to respond with stress erythropoiesis.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30102 - Immunology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Journal of Allergy and Clinical Immunology

ISSN

0091-6749

e-ISSN

—

Svazek periodika

145

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

5

Strana od-do

1297-1301

Kód UT WoS článku

000523633400028

EID výsledku v databázi Scopus

2-s2.0-85078157735